Our research program is devoted to the study of normal and abnormal emotions with a strong emphasis on fear and anxiety. This research is conducted using psychophysiological, psychopharmacological, and brain imaging techniques. The major areas of investigation include: 1) Studies of explicit cue fear and contextual fear as models for phasic fear and generalized anxiety, respectively; 2) investigations of the effects of psychotropic medications on fear and anxiety in healthy individuals and in clinical groups; 3) development of experimental models of fear and anxiety in humans. The experimental approach is restricted to humans, but this program of research is strongly influenced by theories and methods from animal analogues of emotion, motivation, and associative learning. Thus, the research relies on efforts to translate findings from animal research into human experimentation and studies of psychopathology. 1.) Studies of proximal versus distal or contextual threat as models for phasic fear and generalized anxiety, respectively. Fear is associated with a clearly identifiable, imminent threat, whereas anxiety is a generalized fear without object, an apprehensive anticipation of future potential threats. Our working hypothesis is that fear and anxiety can be modeled by cued fear and contextual fear, respectively. The distinction between cued fear and contextual anxiety was first made in fear conditioning studies in animals. Cued fear is elicited by an explicit stimulus (e.g., a light) that predicts an imminent noxious stimulus (e.g., a shock). Contextual fear is caused by the experimental context (i.e., the cage, the experimental room) where an aversive experiment took place. Given the potential relevance of contextual fear for our understanding of anxiety disorders and the paucity of human research in this area, we are pursuing several areas of investigations focusing on contextual fear. The first one examines factors that are involved in the modulation of contextual fear. We have reported in several studies that predictability mitigates contextual fear using instructed fear as well as conditioning procedures. Contextual fear is increased by unpredictability as long as the aversive event is sufficiently unpleasant. We are currently following-up on these findings in three areas. One investigates brain mechanisms mediating cued fear to signaled shocks and contextual anxiety to unpredictable shock in an fMRI study. Preliminary findings indicate reduced activation in medial prefrontal structures during unpredictable shocks. A second investigation assesses the effects of psychopharmacological agents. A third area explores the relevance of these findings to psychopathology by investigating contextual fear in individuals diagnosed with an anxiety disorder or selected for low or high trait anxiety. Preliminary evidence shows that high trait anxious subjects and patients with generalized anxiety disorders, panic disorder or PTSD show increased contextual fear.. 2.) Psychopharmacologic investigations. In order to validate our experimental models of anxiety, we need to show the efficacy of drugs that alleviate anxiety in patients with anxiety disorders. Consistent with our hypothesis, we have shown that the benzodiazepine alprazolam reduces contextual anxiety without affecting cued fear. On the other hand, the SSRI citalopram increased both types of aversive responses. This is consistent with the clinical experience that SSRI are initially anxiogenic. They become anxiolytic only after several weeks of chronic treatments. 3.) Development of experimental models of human fear and anxiety states. One important aspect of our program of research is to develop procedures to study fear and anxiety in humans. Despite important recent progress, we have become increasingly dissatisfied with traditional fear conditioning protocols. There are two main issues: conditioned responses are weak (i.e., they extinguished rapidly) and they are not well retained over time. In addition, the stimuli used in these studies are somewhat unsophisticated (e.g., geometric shapes presented on a monitor). These problems limit the development of meaningful fear conditioning procedures, more particularly for psychopharmacology and contextual fear studies. We have embarked on a project that uses computer-generated virtual reality to investigate fear conditioning and have recently documented for the first time context conditioning in virtual environment (Baas et al 2004). In a new virtual reality study, we now report that more anxiety and more avoidance are conditioned to environments where shocks are administered unpredictably, compared to predictably.